MX2014010040A

MX2014010040A - Oral pharmaceutical compositions of dabigatran etexilate.

Info

Publication number: MX2014010040A
Application number: MX2014010040A
Authority: MX
Inventors: Pratibha S Pilgaonkar; Maharukh T Rustomjee; Anilkumar S Gandhi
Original assignee: Esteve Labor Dr
Priority date: 2012-02-21
Filing date: 2013-02-21
Publication date: 2014-11-10
Also published as: JP6215239B2; NZ628301A; CA2864423A1; US20150030680A1; US11013729B2; PL2817000T3; CN110123774A; HUE056194T2; SI2817000T1; JO3616B1; AU2013224146B2; US11752142B2; AU2013224146A1; EP2817000A1; BR112014020474A2; RU2633482C2; EP3858337A3; US20240139168A1; LT2817000T; KR102090242B1

Abstract

Compositions comprising a mixture of at least two types of particles wherein a) the first type of particles comprise dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof; and b) the second type of particles comprise at least one pharmaceutically acceptable organic acid, use of said compositions in the reduction of the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation and/or in the prevention of venous thromboembolic events in adult patients who have undergone elective total hip replacement surgery or total knee replacement surgery and processes for the preparation of said compositions.

Description

ORAL PHARMACEUTICAL COMPOSITIONS OF DABIGATRÁN ETEXILATO DESCRIPTION Field of the invention The present invention relates to oral pharmaceutical compositions comprising dabigatran etexilate or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION Atrial fibrillation is the most common cardiac arrhythmia that is characterized by an abnormal heart rhythm. It is considered to be a common cause of irregular heartbeat and can cause strokes and other systemic embolic events, eventually leading to death. It has been observed that the incidence of atrial fibrillation increases with age and almost 6% of individuals over 65 years of age are affected, while the prevalence is about 8% in individuals over 80 years of age. The lack of organized cardiac contractions in atrial fibrillation usually results in some stagnant blood in the left atrium or left atrial appendage. This lack of movement of the blood leads to the formation of thrombi or to blood coagulation. Therefore, patients with atrial fibrillation are at an increased risk of developing clots, which increases the risk of developing stroke and other systemic embolic events. Since the consequence of stroke or systemic embolism is devastating, a primary goal of therapy for atrial fibrillation is to reduce the risk of arterial thrombus formation and thromboembolism. Are used mainly anticoagulants such as warfarin in case of atrial fibrillation along with other medications such as beta-blockers and calcium channel blockers or some non-invasive methods of rhythm control. Although it has been shown that anticoagulant therapy with warfarin significantly reduces the incidence of stroke or systemic embolism, it is found that its use is complicated due to multiple interactions with diet and drugs, bleeding possibilities that are difficult to control, the need for frequent monitoring in the laboratory, etc. Therefore, the use of a newer safe and effective anticoagulant is necessary.

Direct thrombin inhibitors are another class of anticoagulants that act by directly inhibiting the thrombin enzyme and are expected to replace heparin (and derivatives) and warfarin in various clinical situations. Thrombin, a serine protease protein formed by catalytic cleavage of prothrombin, converts soluble fibrinogen into insoluble fibrin strands and also catalyzes many other coagulation-related reactions. Direct thrombin inhibitors inhibit thrombin including fibrin-bound thrombin, thereby delimiting the growth of thrombi, provide predictable anticoagulant responses because they do not bind to plasma proteins and have no drug interactions. Depending on their interaction with the thrombin molecule, there are bivalent as well as univalent types of direct thrombin inhibitors, some of which are of clinical use, while others are in clinical development.

Dabigatran is a potent, reversible, univalent direct thrombin inhibitor. Reduces the risk of developing cerebrovascular accident and systemic embolism in patients with non-valvular atrial fibrillation. It is also useful in the primary prevention of venous thromboembolic events in adult patients who have undergone total knee arthroplasty surgery or scheduled total hip arthroplasty surgery. Dabigatran inhibits platelet-induced platelet-induced thrombin, free thrombin, and fibrin-bound thrombin. Dabigatran was first disclosed in WO98 / 37075, which claimed compounds with a thrombin inhibitory effect and the effect of prolongation of thrombin time, under the name of N- (2-pyridyl) -N- ( 2-Ethoxycarbonylethyl) amides of l-methyl-2- [N- [4- (Nn-hexyloxycarbonylamido) phenyl] aminomethyl] benzimidazol-5-ylcarboxylic acid.

Currently dabigatran is available as dabigatran etexilate mesylate (DEM) under the trade name Pradaxa® from Boehringer Ingelheim as oral capsules for immediate release at concentrations of 75 mg and 110 mg (in Europe) and 75 mg and 150 mg (in the United States). ) to be administered twice a day. DEM is a salt form of the prodrug dabigatran etexilate which after oral administration is absorbed and converted to dabigatran by hydrolysis catalyzed by esterases in the liver. DEM is a yellow-white to yellow non-hygroscopic powder that exists in two anhydrous polymorphic forms, Form I and II, which are described in WO 2005/028468. The aqueous solubility of DEM depends strongly on the pH with a fairly high solubility in acidic media and a very low solubility in neutral and basic media while the solubility in water is 1.8 mg / ml. The absolute bioavailability of dabigatran after oral administration of dabigatran etexilate is approximately 3-7% and the elimination half-life is 12-17 hours. DEM is a drug of class II BCS, which indicates poor aqueous solubility but good membrane permeability. DEM is stable in the solid state and is not sensitive to irradiation with light but predominantly undergoes degradation by hydrolytic routes in the presence of moisture. It is also sensitive to acids.

Due to these physicochemical and biopharmaceutical properties of DEM, some attempts have been made to provide compositions of DEM that are stable and / or provide desirable in vitro bioavailability and release.

US Patent Application 2006/0183779 A1 discloses DEM pharmaceutical compositions for oral administration in the form of microgranules comprising (a) substantially spherical core material comprised of one or more pharmaceutically acceptable organic acids with a water solubility of > 1 g / 250 ml at 20 ° C such as tartaric acid; and (b) a layer of active substance containing one or more binders and optionally a separation agent, which encloses said core material. The separation agent layer or insulating layer separates the acid core from the layer containing the active substance. The layer of active substance can be enclosed in turn in a coating that increases the abrasion resistance and the expiration term of the microgranules. Such layered microgranules are later filled into hard capsules. However, the method of preparing the microgranules in layers is complicated, takes a long time and is uneconomical.

U.S. Patent Application 2005/0038077 discloses a tablet comprising dabigatran etexilate or a pharmaceutically acceptable salt thereof; one or more pharmaceutically acceptable organic acids with a solubility in water of > 1 g / 250 ml at 20 ° C and a pharmaceutically acceptable excipient or filler. However, due to the presence of an organic acid in close contact with the active ingredient in a tablet composition if no special step is undertaken to separate from one another, it can render the active ingredient highly susceptible to hydrolysis in the presence moisture.

Previous attempts only provided DEM compositions, which are either tedious or require a lot of technology to prepare or are not likely to remain stable throughout the expiration term of the product. Therefore, there is a need to prepare alternative dabigatran etexilate compositions which are stable, easy or convenient to prepare, and provide the desired in vitro release and bioavailability.

The present inventors after rigorous experimentation provide oral compositions of dabigatran etexilate comprising a mixture of at least two types of particles and optionally at least one pharmaceutically acceptable excipient, wherein a) the first type of particles comprise the active agent; b) the second type of particles comprises at least one pharmaceutically acceptable organic acid; and c) optionally at least one type of particles are coated with a protective coating layer. Such compositions are chemically and polymorphically stable, provide desired in vitro and in vivo performances and can be prepared by a simple, non-tedious and cost-effective process. In particular, the compositions of the present invention provide fast dissolution particularly at points of previous time compared to a formulation having a particle / microgranule type. Such a faster dissolution at earlier time points can guarantee the availability of more quantity of active principle especially when (a) the absorption of the active principle is fast with Tmax faster (~ 45 minutes - 1 hour), (b) it is implied a significant bioactivation and (c) negligible and variable absorption at higher pH.

Detailed description of the invention The present invention provides, in one of its aspects, pharmaceutical compositions, preferably for oral administration, which comprise a mixture of at least two types of particles and optionally at least one pharmaceutically acceptable excipient, in which a) the first type of particles comprise dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof; and b) the second type of particles comprise at least one pharmaceutically acceptable organic acid.

In a particular embodiment, the present invention provides pharmaceutical compositions, preferably for oral administration, comprising a mixture of at least two types of particles and optionally at least one pharmaceutically acceptable excipient, wherein a) the first type of particles comprise dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof; b) the second type of particles comprises at least one pharmaceutically acceptable organic acid; and c) optionally at least one type of particles are coated with a protective coating layer.

The compositions of the present invention are stable, easy to prepare and provide the desired in vitro release of the active ingredient.

The first type of particles present in the composition of the present invention comprise dabigatran etexilate. Dabigatran etexilate can be used in the compositions of the present invention as a free base (3- [(2- {4- (hexyloxycarbonylamino-imino-methyl) -phenylamino] methyl] ethyl] -l-methyl-lH ethyl ester. -benzimidazole-5-carbonyl) -pyridin-2-yl-amino-propionic acid) or in the form of pharmaceutically acceptable salts, polymorphs, solvates, hydrates thereof. For purposes of concision, the term dabigatran etexilate is used in this specification to designate any of the forms mentioned above except when the term is further qualified (ie, dabigatran etexilate mesylate). Whenever it is necessary to designate the free base of dabigatran etexilate, the term "dabigatran etexilate (free base)" is used.

The term "pharmaceutically acceptable salt" refers to those salts which, according to medical criteria, are suitable for use in contact with the tissues of humans and other mammals without excessive toxicity, irritation, allergic response and the like. Pharmaceutically acceptable salts are well known in the art.

In one embodiment, the amount of dabigatran etexilate (expressed as dabigatran etexilate mesylate) in the composition can vary between about 0.01% by weight and about 90% by weight, based on the total weight of the composition. In another embodiment, the amount of dabigatran etexilate in the composition can vary between about 0.02% by weight and about 85% by weight, based on the total weight of the composition. In still In another embodiment, the amount of dabigatran etexilate in the composition can vary between about 0.05% by weight and about 80% by weight, based on the total weight of the composition.

In one embodiment, the compositions of the present invention may be in the form of unit dosage forms comprising from 50 mg to 200 mg of dabigatran etexilate mesylate, preferably from 75 mg to 150 mg, more preferably 75 mg, 110 mg or 150 mg .

In one embodiment of the present invention, dabigatran etexilate is used in the form of the mesylate salt, ie dabigatran etexilate mesylate.

In a particular embodiment of the present invention, dabigatran etexilate is used in the form of the polymorphic form I of dabigatran etexilate mesylate (as described in WO 2005/028468).

In another particular embodiment of the present invention, dabigatran etexilate is used in the form of the polymorphic form II of dabigatran etexilate mesylate (as described in WO 2005/028468).

The oral pharmaceutical composition of the present invention comprises a mixture of at least two types of particles and optionally at least one pharmaceutically acceptable excipient, a first type of particles comprising dabigatran etexilate and a second type of particles comprising at least one pharmaceutically acceptable organic acid.

In a preferred embodiment of the present invention, the first type of particles comprising dabigatran etexilate is free of organic and inorganic acids.

In a preferred embodiment of the present invention, the first type of particles comprising dabigatran Etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof, also comprise at least one pharmaceutical excipient.

In the most preferred embodiment of the present invention, said first type of particles comprising dabigatran etexilate mesylate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof, also comprise one or more excipients selected from the group consisting of binders, diluents and / or lubricants.

In a particular embodiment, said first type of particles comprise at least one binder, preferably microcrystalline cellulose.

In another particular embodiment, said first type of particles comprise at least one disintegrant, preferably selected from croscarmellose sodium or crospovidone.

In another particular embodiment, said first type of particles comprise at least one diluent, preferably selected from mannitol or lactose.

In another particular embodiment, said first type of particles comprise at least one binder, preferably microcrystalline cellulose, a disintegrant, preferably selected from croscarmellose sodium or crospovidone and a diluent, preferably selected from mannitol or lactose.

In another preferred embodiment of the present invention, the second type of particles comprising at least one pharmaceutically acceptable organic acid is free of dabigatran etexilate.

In the most preferred embodiment of the present invention, the first type of particles comprising dabigatran Etexilate is free of acids and the second type of particles comprising at least one pharmaceutically acceptable organic acid is free of dabigatran etexilate.

In another preferred embodiment of the present invention, the second type of particles comprises tartaric acid, preferably in the form of microgranules with a particle size of between 100 and 900 micrometers, more preferably between 400 and 700 micrometers.

An acid is a substance that releases hydrogen ions and lowers the pH of an aqueous solution.

Organic acids that may be employed in the present composition include, but are not limited to, tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid, aspartic acid and the like or combinations thereof including hydrates and acid salts thereof.

In one embodiment, the organic acid is present in the composition of the present invention in an amount of about 2% by weight to about 95% by weight of the composition. In another embodiment, the organic acid is present in the composition of the present invention in an amount of about 5% by weight to about 90% by weight of the composition. In a further embodiment, the organic acid is present in the composition of the present invention in an amount of about 10% by weight to about 85% by weight of the composition.

In one embodiment, at least 90% by weight, preferably at least 95% by weight, more preferably at least 99% by weight and still more preferably 100% by weight of the organic acid present in the composition is contained in the second type of particles comprising at least one pharmaceutically acceptable organic acid, the remainder (if any) of the organic acid being added as part of the excipients.

In addition, the oral pharmaceutical compositions of the present invention comprise a mixture of at least two types of particles and optionally at least one pharmaceutically acceptable excipient, wherein optionally at least one type of particles is coated with a protective coating layer. In one embodiment, the first type of particles are coated with a protective coating layer. In another embodiment, the second type of particles are coated with a protective coating layer. In yet another embodiment, the first and second types of particles are coated with a protective coating layer.

The term "protective coating layer" as used herein, is meant to mean a layer of a polymeric or non-polymeric material disposed on the surface of a particle core in order to avoid direct contact of the particle core with its environment.

In one embodiment, the protective coating layer is formed by a pharmaceutically acceptable polymeric or non-polymeric agent or any combination thereof.

The pharmaceutically acceptable polymeric agents used for the protective coating layer include, but are not limited to, cellulose derivatives, derivatives, vinyl polymers and copolymers, gums, polymers, copolymers, esters of acrylic or methacrylic acid or derivatives thereof, and similar or combinations thereof. The cellulose derivatives that may be employed, include, but are not limited to, methylcellulose, hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, hydroxymethylcellulose, ethylcellulose, hydroxypropyl ethylcellulose, carboxymethylethylcellulose, carboxyethylcellulose, carboxymethylhydroxyethylcellulose, hydroxyethylmethylcarboxymethylcellulose, hydroxyethyl methylcellulose, carboxymethylcellulose, methylhydroxyethylcellulose, methylhydroxypropylcellulose, carboxymethyl sulfoethylcellulose, sodium carboxymethylcellulose, and the like or combinations thereof. The vinyl derivatives, polymers and copolymers thereof that may be employed include, but are not limited to, copolymers of vinyl pyrrolidone, polyvinyl alcohol copolymers (Kollicoat IR), polyvinyl pyrrolidone or combinations thereof. The gums that can be used include, but are not limited to, gum arabic, alginates, guar gum, locust bean gum, carrageenans, pectin, xanthan gum, gellan gum, maltodextrin, galactomannan, karaya gum, and the like, or combinations. The polymers, copolymers, acrylic or methacrylic acid esters or derivatives thereof, which may be employed include, but are not limited to, a) copolymer formed from monomers selected from methacrylic acid, methacrylic acid esters, acrylic acid and esters of acrylic acid, b) copolymer formed from monomers selected from butyl methacrylate, (2-dimethylaminoethyl) methacrylate and methyl methacrylate, c) copolymer formed from monomers selected from ethyl acrylate, methyl methacrylate and ethyl trimethylammonium methacrylate or d) acrylate and methacrylate copolymers with / without a quaternary ammonium group in combination with sodium carboxymethyl cellulose, for example those available from Rohm GmbH under the trademark Eudragit® as Eudragit EPO (copolymer of dimethylaminoethyl methacrylate; basic butylated methacrylate copolymer), Eudragit RL and RS (trimethylammonioethyl methacrylate copolymer), Eudragit NE30D and Eudragit NE40D (ethyl acrylate-methyl methacrylate copolymer), Eudragit RD 100 (ammonium methacrylate copolymer with sodium carboxymethylcellulose); or similar or any combination thereof.

The pharmaceutically acceptable non-polymeric agents used for the protective coating layer include, but are not limited to C8-C22 fatty acids, C8-C22 fatty alcohols, fats, in particular mono, di or triesters of glycerol and C8-C22 fatty acids, waxes, and the like, or combinations thereof. Fatty acids that can be employed include, but are not limited to, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, rapeseed oil hydrogenated, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, and the like, and mixtures thereof. The long chain monohydric alcohols that may be employed include, but are not limited to, cetyl alcohol, stearyl alcohol and mixtures thereof. Waxes that may be employed include, but are not limited to, spermaceti wax, carnauba wax, Japan wax, wax of lyric wax, wax of bees, wax of bees, wax of China, wax of shellac, wax of lanolin, sugarcane wax, candelilla wax, paraffin wax, microcrystalline wax, petrolatum wax, Carbowax, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, monopalmitate glyceryl, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecenoate, glyceryl behenate and the like or mixtures thereof.

In a further embodiment, in addition to polymeric or non-polymeric pharmaceutically acceptable agent or any combination thereof, the protective coating layer may optionally further comprise one or more pharmaceutically acceptable excipients such as, but not limited to, plasticizer, anti-adherent agent, pigment, and the like, or combinations thereof. A plasticizer that can be employed includes, but is not limited to, triethyl citrate, acetyl triethyl citrate, propylene glycol, polyethylene glycol, acetyl tributyl citrate, acetylated monoglycerides, glycerin, triacetin, phthalate esters (eg, diethyl phthalate). , dibutyl phthalate), castor oil, sorbitol and dibutyl sebacate or a combination thereof. A non-stick agent that may be employed includes, but is not limited to, talc or glyceryl monostearate. A pigment may be employed such as, but not limited to, titanium dioxide, iron oxide, or a mixture thereof.

The protective coating layer can optionally be applied on at least one type of particles of the present invention. For example, the protective coating layer is applied to the first type of particles comprising dabigatran etexilate in free base form or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof.

In a preferred embodiment of the present invention, the protective coating layer is coated on the second type of particles comprising at least one pharmaceutically acceptable organic acid. In a particular embodiment, said coating layer comprises hydroxypropylmethylcellulose and talc.

In another embodiment, both particles are coated with said protective coating layer.

The protective coating layer may optionally be applied on at least one type of particles of the present invention in any suitable equipment in which the coating can be achieved, such as, but not limited to, coating pan, conventional film coating apparatus or a fluidized bed apparatus, or the like. In addition, in one embodiment, the protective coating layer can be applied from an aqueous or organic solution or dispersion. In another embodiment, the particles to be coated with the protective coating layer can be coated to a weight increase of from about 2% to about 50% by weight.

In one embodiment, in order to reduce any damage to the protective overcoat layer during transfer into capsules, coated with the protective cover layer particles may be coated with sealed additionally with conventional agents film forming pharmaceutically acceptable they can optionally combined with plasticizers or pigments. Suitable film-forming agents include, but are not limited to, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polymers, copolymers or esters of acrylic and methacrylic acid, and the like or combinations thereof. The plasticizers or pigments mentioned above they can optionally be used with the film-forming agents.

The compositions of the present invention comprise a mixture of at least two types of particles and optionally at least one pharmaceutically acceptable excipient. In a further embodiment, the first type of particles comprising dabigatran etexilate may optionally further comprise at least one pharmaceutically acceptable excipient. In another embodiment, the second type of particles comprising at least one organic acid may optionally further comprise at least one pharmaceutically acceptable excipient. In yet another embodiment, at least two types of particles that are present in the pharmaceutical composition optionally further comprise at least one pharmaceutically acceptable excipient.

The pharmaceutically acceptable excipients that can be incorporated into the composition of the present invention include, but are not limited to, binders, disintegrants, diluents, surfactants, glidants, lubricants, and the like or combinations thereof.

The term "disintegrant" as used herein is intended to mean a compound used in solid dosage formulations to promote breakdown of the solid mass to give smaller particles that disperse or dissolve more easily. Disintegrants for example include, by way of example and without limitation, natural starch, modified or pregelatinized starch, modified starches (such as sodium starch glycolate) and partially pregelatinized starches (such as Starch 1500), polyvinylpyrrolidone, crospovidone, croscarmellose sodium , calcium silicate clays, such as bentonite, microcrystalline cellulose, goiíias such as agar, guar, locust bean, karaya, pectin, tragacanth, alginates, ion exchange resins (such as Polacrilin potassium, Polacrilex) Neusilin, hydroxypropylcellulose with a low degree of substitution and the like, combinations thereof and other such materials known by those of ordinary skill in the art.

The term "binders" as used herein is intended to mean substances used to cause adhesion of powder particles in granulations. Examples of suitable binders include, but are not limited to celluloses such as microcrystalline cellulose, modified celluloses (such as hydroxypropyl cellulose with low degree of substitution, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC or hypromellose or), hydroxyethylcellulose, hydroxyethylcellulose methylcellulose, ethylcellulose, cellulose gum, xanthan gum, sugars (such as sucrose, glucose, amylose, maltodextrin, dextrose and the like), starches such as corn starch or potato starch, partially pregelatinized starches (such as starch 1500), poly ( vinyl acetate) (Kollicoat SR), graft copolymer of poly (vinyl alcohol) -polietilenglicol (Kollicoat IR), copovidone, crosslinked polyvinylpyrrolidone, acrylic acid polymer (Carbopol), poloxamer, polycarbophil, poly (ethylene oxide), polyethylene glycol , and the like, combinations thereof and other materials known to those of ordinary skill in the art.

The term "diluent" or "filler" as used herein is meant to mean inert substances used as fillers to create the mass, flow properties and compression characteristics desired in the preparation of solid dosage formulations. Examples of suitable diluents include, but are not limited to, microcrystalline cellulose, co-processed microcrystalline celluloses (such as Avicel Cl-611, Avicel RC-581, Avicel RC591, Avicel CE, Avicel DG, Avicel HFE), lactose, sucrose, xylitol, mannitol, maltose, polyols, fructose, guar gum, sorbitol, magnesium hydroxide, dibasic calcium phosphate, kaolin, calcium sulfate, carrageenans, chitosan, pectinic acid, sodium alginate, aluminum magnesium silicate, calcium carbonate and the like , combinations thereof and others of such materials known to those of ordinary skill in the art.

The term "lubricant" as used herein is meant to mean substances used in solid dosage formulations to reduce friction during compression of the solid dosage. Such compounds include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, stearic acid, talc, mineral oil and sodium stearyl fumarate, combinations thereof and other such materials known to those of ordinary skill in the art. technique .

The tablet compositions of the invention may also include a glidant. The term "glidant" as used herein is meant to mean agents used in solid dosage formulations to improve the flow properties during compression of the tablet and to produce an anti-caking effect. Such compounds include, but are not limited to, colloidal silica, silica gel, precipitated silica, calcium silicate, magnesium silicate, corn starch, talc, combinations of the same and other such materials known to those of ordinary skill in the art.

The term "surfactant" as used herein is meant to mean substances used to reduce the surface tension of the aqueous solutions comprising them. Examples of surfactants include, but are not limited to, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester, mixtures of the same and other such materials known to those of ordinary skill in the art.

The compositions of the present invention comprise a mixture of at least two types of particles and optionally at least one pharmaceutically acceptable excipient, the first type of particles comprising dabigatran etexilate and the second type of particles comprising at least one organic acid.

The term "particle" as used herein is meant to mean any solid or semi-solid part of a substance or composition having defined physical limits. Examples of particles include, but are not limited to, powder, granules, microgranules, beads, mini-tablets or the like. The granules can be prepared by methods such as, but not limited to, wet granulation, melt granulation, dry granulation or roll compaction or the like. In an embodiment of the present invention, microgranules can be prepared using spheronization by extrusion. In another embodiment of the present invention, the dabigatran etexilate present in the first set of particles or at least one organic acid present in the second set of particles can be loaded onto an inert carrier. The inert carrier can be selected from, but not limited to, beads, microgranules, spheres or similar particles that do not contain an active ingredient. Non-limiting examples of inert carrier include microcrystalline cellulose, sugar or silicon dioxide. In yet another embodiment, the particles of the present invention, in powder form, can be incorporated into the compositions of the present invention.

In an embodiment of the present invention, said first type of particles have a particle size between 50 and 1000 microns and said second type of particles have a particle size comprised between 100 and 1000 microns.

The compositions of the present invention comprise from about 5% to about 100% by weight of the mixture of at least two types of particles. The ratio of the first and second particle types is from about 1:99 to about 99: 1.

The term "composition" or "formulation" has been used interchangeably for the purpose of the present invention. The term "dosage form" as used herein is meant to mean a pharmaceutical composition that is suitable for administration to a patient. In one embodiment, the compositions of the present invention may be in the form of capsules, tablets, mini-tablets, stick formulation, dispersible tablets, dry suspension for reconstitution, powder or granule for solution or suspension, granules, and the like or any combination thereof. same. Depending on the final dosage form, The compositions of the present invention may comprise suitable pharmaceutically acceptable excipients such as those mentioned above or some additional ones such as, but not limited to, sweeteners, flavors, colorants and the like or combinations thereof. Furthermore, within the scope of the invention it is contemplated that the dosage form may be encapsulated or coated. In one embodiment, the composition of the present invention is in the form of a capsule. Capsules include, for example, hard gelatine capsules or hydroxypropylmethylcellulose and the like. In a further embodiment, the compositions of the present invention can be manufactured using conventional techniques known in the art.

The term "unit dosage form" refers to a physically differentiated unit suitable as a unit dosage for a human patient such as a capsule, a tablet or a vial.

In another aspect, the present invention provides a unit dosage form prepared from the aforementioned compositions comprising two types of particles.

The compositions of the present invention provide flexibility in the combination of at least two types of particles to achieve different release patterns. In one embodiment, the compositions of the present invention provide tailored in vitro profiles and corresponding in vivo profiles. In a further embodiment, the compositions of the present invention can provide tailor-made profiles in which the dissolution of the compositions of the present invention can be faster at initial time points compared to formulations having only a single type of particles comprising either dabigatran etexilate or pharmaceutically acceptable salts thereof as organic acid. Without being limited to any theory, it is believed that such a faster dissolution at earlier time points can guarantee the availability of more quantity of active principle especially when (a) the absorption of the active principle is rapid with Tmax faster (~ 45 minutes - 1 hour), (b) a significant bioactivation is involved for the action of dabigatran and (c) a negligible and variable absorption is observed at a higher pH.

In another aspect, the present invention provides a process for the preparation of a composition comprising the two types of particles described above comprising the step of mixing said first type of particles and said second type of particles with at least one pharmaceutically acceptable excipient. In a particular embodiment of the present invention, said first type of particles are prepared by granulation. In one embodiment, the method of preparing the compositions of the present invention comprises the steps of (i) combining dabigatran etexilate and at least one pharmaceutically acceptable excipient such as diluent; (ii) granulating the combination of step (i) with a binder solution to form granules of the active agent; (iii) combining at least one organic acid and at least one pharmaceutically acceptable excipient such as diluent; (iv) granulating the combination of step (iii) with a binder solution to form organic acid granules; (v) coating the organic acid granules with a protective coating layer; (vi) combining the granules of step (ii) with the coated granules of step (v) to form a mixture of at least two types of granules; (vii) optionally combining the mixture of at least two types of granules of step (vi) with at least one pharmaceutically acceptable excipient; (viii) lubricate the combination of stage (vii); (ix) filling the lubricated mixture of step (viii) into suitable hard capsules.

In another embodiment, the method of preparing the compositions of the present invention comprises the steps of (i) combining dabigatran etexilate and at least one pharmaceutically acceptable excipient such as diluent; (ii) granulating the combination of step (i) with a binder solution to form granules of the active agent; (iii) combining at least one organic acid and at least one pharmaceutically acceptable excipient such as diluent; (iv) granulating the combination of step (iii) with a binder solution to form organic acid granules; (v) coating the granules of active agent with a protective coating layer; (vi) combining the granules of step (iv) with the coated granules of step (v) to form a mixture of at least two types of granules; (vii) optionally combining the mixture of at least two types of granules of step (vi) with at least one pharmaceutically acceptable excipient; (viii) lubricate the combination of stage (vii); (ix) filling the lubricated mixture of step (viii) into suitable hard capsules.

In yet another embodiment, the method of preparing the compositions of the present invention comprises the steps of (i) combining dabigatran etexilate and at least one pharmaceutically acceptable excipient such as diluent; (ii) granulating the combination of step (i) with a binder solution to form granules of the active agent; (iii) combining at least one organic acid and at least one pharmaceutically acceptable excipient such as diluent or binder; (iv) extruding and spheronizing the combination of step (iii) to form microgranules of organic acid; (v) coating the organic acid microgranules of step (iv) with a protective coating layer; (vi) combining the granules of step (ii) with the coated microgranules of step (v) to form a mixture of at least two types of particles; (vii) optionally combining the mixture of at least two types of granules of step (vi) with at least one pharmaceutically acceptable excipient; (viii) lubricate the combination of stage (vii); (ix) filling the lubricated mixture of step (viii) into suitable hard capsules.

In a further aspect, the present invention provides the use of the pharmaceutical composition of dabigatran etexilate of the present invention for the manufacture of a medicament for reducing the risk of developing stroke and systemic embolism in patients with non-valvular atrial fibrillation and / or preventing venous thromboembolic events in adult patients who have undergone surgery for total knee arthroplasty or scheduled total hip arthroplasty surgery.

In yet another aspect, the present invention provides a method for reducing the risk of developing stroke and systemic embolism in patients with non-valvular atrial fibrillation and / or preventing venous thromboembolic events in adult patients who have undergone total knee arthroplasty surgery or scheduled total hip arthroplasty surgery, which comprises administering to the subject in need thereof pharmaceutical compositions of dabigatran etexilate of the present invention.

In another embodiment of the present invention, dabigatran etexilate may be combined with other active agents or pharmaceutically acceptable salts thereof including, but not limited to, atorvastatin, dipyridamole, mopidamol and the like or combinations thereof.

The invention is further illustrated by the following examples, which are for illustrative purposes and should not be construed as limiting the scope of the invention in any way.

And os Example 1: Formulation of oral capsule of dabigatran etexilate mesylate A) Preparation of coated microgranules of tartaric acid (a) Preparation of microgranules of tartaric acid Table 1: Composition of microgranules of tartaric acid * not present in the final product Procedure: Tartaric acid and microcrystalline cellulose were combined and to this combination was added hydroxypropyl cellulose solution in isopropyl alcohol to obtain a wet mass. This moist mass was extruded, spheronized, dried and sieved to give microgranules. These microgranules were then coated with a protective coating layer as follows to give coated microgranules of tartaric acid. (b) Preparation of coated microgranules of tartaric acid Table 2: Composition of microgranules of tartaric acid * not present in the final product Procedure: Microgranules of tartaric acid prepared as above were coated with dispersion of hydroxypropylcellulose and talc in isopropyl alcohol. The coated microgranules were then dried to give coated microgranules of tartaric acid.

B) Preparation of granules of dabigatran etexilate mesylate Table 3: Composition of granules of dabigatran etexilate mesylate * not present in the final product Procedure: Dabigatran etexilate mesylate, microcrystalline cellulose, lactose anhydrous and crospovidone were combined. The combination was granulated using a solution of hydroxypropylcellulose in isopropyl alcohol. The granules were sized and sieved to form granules of dabigatran etexilate mesylate.

C) Preparation of oral capsule formulation of dabigatran etexilate mesylate Table 4: Formulation composition of dabigatran etexilate mesylate capsule Procedure: Granules of dabigatran etexilate mesylate prepared according to the composition of table 3 above and coated microgranules of tartaric acid prepared according to table 2 above were combined. The combination was lubricated with sodium stearyl fumarate and filled into capsules by means of a capsule filling machine.

Example 2: Formulation of oral capsule of dabigatran etexilate mesylate A) Preparation of microgranules of tartaric acid Table 5: Composition of microgranules of tartaric acid * not present in the final product Procedure: Tartaric acid and microcrystalline cellulose were combined and to this combination was added hydroxypropyl cellulose solution in isopropyl alcohol to obtain a wet mass. This moist mass was extruded, spheronized, dried and sieved to give microgranules. Then these microgranules were coated using a layer of protective coating as follows to give coated tartaric acid microgranules.

B) Preparation of granules coated with dabigatran etexilate mesylate (a) Preparation of granules of dabigatran etexilate mesylate Table 6: Composition of granules of dabigatran etexilate mesylate * not present in the final product Procedure: Dabigatran etexilate mesylate, microcrystalline cellulose, lactose anhydrous and crospovidone were combined. The combination was granulated using a solution of hydroxypropylcellulose in isopropyl alcohol. The granules were sized and sieved to form granules of dabigatran etexilate mesylate. (b) Preparation of granules coated with dabigatran etexilate mesylate Table 7: Composition of granules coated with dabigatran etexilate mesylate not present in the final product Procedure: Granules of dabigatran etexilate mesylate prepared according to the aforementioned process were coated with a coating dispersion of polyvinylpyrrolidone and talc in isopropyl alcohol to form granules of coated dabigatran etexilate mesylate.

C) Preparation of oral capsule formulation of dabigatran etexilate mesylate Table 8: Formulation composition of dabigatran etexilate mesylate capsule Procedure: Granules of dabigatran etexilate mesylate prepared according to table 7 above and coated microgranules of tartaric acid prepared according to table 5 above were combined. The combination was lubricated with sodium stearyl fumarate and filled into capsules by means of a capsule filling machine.

Example 3: Comparative evaluation of two formulation approaches for dabigatran etexilate mesylate The two formulation approaches for dabigatran etexilate mesylate were evaluated as shown below: (i) The first approach being that of the present invention having two types of particles / microgranules (one of dabigatran etexilate mesylate and the other of organic acid) and (ii) the second approach having a particle / microgranule type having both dabigatran etexilate mesylate and organic acid. This formulation was prepared according to the teachings of US 2006/074056 and, in particular, example 1. Formulation (B) (A) Preparation of formulation A having two types of particles / microgranules (ie granules of dabigatran etexilate mesylate and microgranules of tartaric acid with sealing coating) Table 17: Composition of granules of dabigatran etexilate mesylate Table 18: Composition of microgranules of tartaric acid with sealing coating Process : (i) Preparation of the granules part of dabigatran etexilate mesylate The heavy amount of dabigatran etexilate mesylate was charged in the granulator and granulated using isopropyl alcohol. The granules were further dried in a fluidized bed dryer. The granules were then sized, sieved and combined with microcrystalline cellulose, croscarmellose sodium in a suitable mixer to give the granules part of dabigatran etexilate mesylate. (ii) Preparation of microgranules of tartaric acid with sealing coating Hydroxypropylcellulose was added to a suitable amount of isopropyl alcohol-water mixture with continuous stirring to obtain a clear solution. Lactose was added to this solution and mixed, followed by addition of talc and stirring. The suspension thus formed was filtered through a suitable screen and sprayed with continuous agitation onto the tartaric acid pellets using a fluidized bed coating apparatus with Wurster column to achieve the desired weight gain. The coated tartaric acid microgranules were then dried.

The granules of dabigatran etexilate mesylate and the microgranules of tartaric acid with sealing coating lubricated in capsules were filled using the automatic capsule filling machine in HPMC capsules of size 0.

(C) Comparative evaluation of the dissolution profiles of the formulation of the present invention having two types of particles / microgranules (formulation A above) and formulation having a particle / microgranule type (formulation B above) The dissolution profiles of the formulations in media of 0.01 N HCl at pH 2 at 100 rpm of type I of the USP (basket) are as shown for A and B below: of liberation Ormulation time A rormulation B (minutes) (two types of (a type of Darticles /? Articulas / The evaluation Comparison of dissolution profiles of the formulation of the present invention having two types of particles / microgranules (formulation A above) and formulation having a particle / microgranule type (formulation B above) indicates that the formulations of the present invention which have two types of particles / microgranules can provide a faster dissolution particularly at earlier time points compared to the formulation having a particle / microgranule type. Such faster dissolution at earlier time points can guarantee the availability of more quantity of active principle especially when (a) the absorption of the active principle is fast with Tmax faster (~ 45 minutes - 1 hour), (b) significant bioactivation is involved and (c) negligible and variable absorption at higher pH.

Claims

1. Composition comprising a mixture of at least two types of particles, wherein a) the first type of particles comprises dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof; and b) the second type of particles comprise at least one pharmaceutically acceptable organic acid.

2. Composition according to claim 1, wherein at least one type of particles are coated with a protective coating layer.

3. Composition according to any one of claims 1 and 2, further comprising at least one pharmaceutically acceptable excipient.

4. Composition according to any preceding claim, wherein said first type of particles is free of acids.

5. Composition according to any preceding claim, wherein said second type of particles is free of dabigatran etexilate.

6. Composition according to any preceding claim, comprising from 0.01% by weight to 90% by weight of dabigatran etexilate (expressed as dabigatran etexilate mesylate).

7. Composition according to any preceding claim, wherein at least 90% by weight of the organic acid present in the composition is contained in said second type of particles and the remainder (if any) of the organic acid forms part of the pharmaceutically acceptable excipients.

8. Composition according to any preceding claim, wherein said first type of particles are coated with a protective coating layer.

9. Composition according to any preceding claim, wherein said second type of particles are coated with a protective coating layer.

10. Composition according to any preceding claim, comprising from 2% by weight to 95% of said at least one pharmaceutically acceptable organic acid.

11. Composition according to any preceding claim, wherein at least 90% by weight of the organic acid present in the composition is contained in said second type of particles, the remainder (if any) being part of the organic acid of said excipients.

12. Unit dosage form prepared from a composition according to any preceding claim, comprising from 50 mg to 200 mg of dabigatran etexilate mesylate.

13. Composition according to any one of claims 1 to 11, or unit dose according to claim 12, for use in reducing the risk of developing stroke and systemic embolism in patients with non-valvular atrial fibrillation and / or in the prevention of thromboembolic events venous in adult patients who have undergone total knee arthroplasty surgery or scheduled total hip arthroplasty surgery.

14. Use of a composition according to any one of claims 1 to 11, or unit dose according to claim 12, for the preparation of a medicament for reducing the risk of developing stroke and systemic embolism in patients with non-valvular atrial fibrillation and / or to prevent venous thromboembolic events in adult patients who have undergone surgery for total knee arthroplasty or total hip arthroplasty surgery.

15. Method to reduce the risk of developing stroke and systemic embolism in patients with non-valvular atrial fibrillation and / or to prevent venous thromboembolic events in adult patients who have undergone total knee arthroplasty surgery or scheduled total hip arthroplasty surgery, which comprises administering to the subject in need thereof a composition according to any one of claims 1 to 11, or a unit dose according to claim 12.

16. Process for the preparation of a composition according to any one of claims 3 to 11, comprising the step of mixing said first type of particles and said second type of particles with at least one pharmaceutically acceptable excipient.

17. The process according to claim 16, wherein said first type of particles are prepared by granulation.

18. Process according to claim 17, comprising the steps of: (i) combining dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof and at least one pharmaceutically acceptable excipient; (ii) granulating the combination of step (i) with a binder solution to form granules of dabigatran etexilate; (iii) combining at least one organic acid and at least one pharmaceutically acceptable excipient; (iv) granulating the combination of step (iii) with a binder solution to form organic acid granules; (v) coating the organic acid granules with a protective coating layer; (vi) combining the granules of step (ii) with the coated granules of step (v) to form a mixture of at least two types of granules; (vii) optionally combining the mixture of at least two types of granules of step (vi) with at least one pharmaceutically acceptable excipient; (viii) adding a lubricant to the combination of step (vii); (ix) filling the lubricated mixture of step (viii) into suitable hard capsules.

19. Process according to claim 17, comprising the steps of: (i) combining dabigatran etexilate in the form of the free base or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof and at least one pharmaceutically acceptable excipient; (ii) granulating the combination of step (i) with a binder solution to form granules of dabigatran etexilate; (iii) combining at least one organic acid and at least one pharmaceutically acceptable excipient; (iv) granulating the combination of step (iii) with a binder solution to form organic acid granules; (v) coating the granules of dabigatran etexilate with a protective coating layer; (vi) combining the granules of step (iv) with the coated granules of step (v) to form a mixture of at least two types of granules; (vii) optionally combining the mixture of at least two types of granules of step (vi) with at least one pharmaceutically acceptable excipient; (viii) adding a lubricant to the combination of step (vii); (ix) filling the lubricated mixture of step (viii) into suitable hard capsules.

20. Process according to claim 17, comprising the steps of: (i) combining dabigatran etexilate in free base form or in the form of pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof and at least one pharmaceutically acceptable excipient; (ii) granulating the combination of step (i) with a binder solution to form granules of dabigatran etexilate; (iii) combining at least one organic acid and at least one pharmaceutically acceptable excipient; (iv) extruding and spheronizing the combination of step (iii) to form microgranules of organic acid; (v) coating the organic acid microgranules of step (iv) with a protective coating layer; (vi) combining the granules of step (ii) with the coated microgranules of step (v) to form a mixture of at least two types of particles; (vii) optionally combining the mixture of at least two types of granules of step (vi) with at least one pharmaceutically acceptable excipient; (viii) adding a lubricant to the combination of step (vii); (ix) filling the lubricated mixture of step (viii) into suitable hard capsules.